What are the possible causes of elevated Rheumatoid Factor (RF) with negative Antinuclear Antibody (ANA) and negative Cyclic Citrullinated Peptide (CCP)?

Causes of Elevated Rheumatoid Factor with Negative ANA and Negative CCP

Elevated RF with negative ANA and negative CCP most commonly occurs in chronic infections (particularly hepatitis B and C), other autoimmune diseases beyond lupus and RA, malignancies, and as an isolated finding in healthy individuals—especially in older adults.

Primary Differential Diagnoses

Infectious Etiologies

• Hepatitis B and C are major causes of isolated RF positivity, with anti-CCP positivity rates of 20.5% for HBV and 32.5% for HCV patients, though these are typically lower titers than seen in RA 1
• Chronic viral infections can trigger RF production without meeting criteria for rheumatoid arthritis 1
• The clinical manifestations of hepatitis B and C show similarities with rheumatic diseases, making differentiation challenging 1

Seronegative Rheumatoid Arthritis

• Seronegative RA accounts for 20-30% of all RA cases and can present with isolated RF positivity without anti-CCP 2
• Only a few RA patients are positive for RF alone (range 18-246 UI/mL) without accompanying anti-CCP antibodies 3
• The absence of anti-CCP does not exclude RA, particularly in early disease 2

Other Autoimmune Conditions

• Sjögren's syndrome can present with RF positivity (9% prevalence) but typically has negative or low-titer ANA in checkpoint inhibitor-induced cases 3
• Systemic lupus erythematosus patients may have anti-CCP in 13.7% of cases, though this typically occurs with positive ANA 4
• Vasculitis of all vessel sizes can present with RF positivity, though ANA and other autoantibodies are rarely positive 3

Non-Rheumatic Causes

• RF positivity is widely observed in advanced age, lymphoproliferative diseases, and as an asymptomatic finding in the general population 5
• Approximately 15% of first-degree relatives of RA patients have RF positivity without clinical disease 2
• Malignancies and chronic inflammatory conditions can trigger RF production 5

Clinical Approach Algorithm

Step 1: Assess RF Titer Level

• RF levels between 20-50 IU/mL have significantly lower rates of rheumatic disease compared to higher titers 5
• RF levels above 500 IU/mL are associated with higher leukocyte counts and increased likelihood of true rheumatic disease 5
• The distribution of rheumatic versus non-rheumatic diagnoses does not differ significantly across RF titer ranges 5

Step 2: Screen for Infectious Causes

• Order hepatitis B and C serology immediately, as these are common causes of isolated RF positivity 1
• Consider tuberculosis screening if risk factors are present 3
• Evaluate for other chronic infections based on clinical presentation 1

Step 3: Evaluate for Clinical Synovitis

• Perform detailed 28-joint examination assessing PIPs, MCPs, wrists, elbows, shoulders, and knees for tenderness and swelling 2
• Document morning stiffness duration and difficulty making a fist 2
• Squeeze test of MCPs and MTPs can help assess for clinical synovitis 2

Step 4: Measure Inflammatory Markers

• Order CRP (preferred over ESR) and complete blood count to assess for active inflammation 2
• Markedly elevated CRP (>90 mg/L) suggests active inflammatory disease requiring aggressive evaluation 2
• Normal inflammatory markers do not exclude rheumatic disease, as acute phase reactants can be normal even in active RA 2

Step 5: Advanced Imaging if Indicated

• Obtain baseline bilateral hand, wrist, and foot X-rays to assess for erosions, which predict RA diagnosis and disease persistence 2
• Consider ultrasound with Power Doppler if clinical examination shows no definite synovitis but suspicion remains high 2
• MRI with IV contrast is more sensitive than ultrasound in early stages and detects bone marrow edema, the best predictor of future disease progression 2

Critical Pitfalls to Avoid

• Do not dismiss the diagnosis based on negative anti-CCP alone, as seronegative RA is common and has similar prognosis to seropositive disease 2
• Do not delay rheumatology referral waiting for positive serology if clinical synovitis is present 2
• Do not rely solely on RF levels to predict rheumatological disease, as RF can be found asymptomatically in the general population 5
• Remember that autoantibodies are often absent in checkpoint inhibitor-induced arthritis, with only 9% RF positivity in some series 3

When to Refer to Rheumatology

• Refer within 6 weeks if definite clinical synovitis is present in at least one joint, regardless of serologic findings 2
• Urgent referral is warranted for Raynaud's phenomenon, digital necrosis, or purpura suggesting vasculitis 6
• Refer if RF positivity occurs with elevated inflammatory markers and clinical symptoms, even without anti-CCP 6
• Watchful waiting with periodic reassessment is appropriate for asymptomatic patients with isolated RF positivity and normal inflammatory markers 6